The rate of neurodegenerative disorders (NDDs) is rising rapidly as the world’s population ages. Conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia are becoming more prevalent and are now the fourth leading cause of death, following heart disease, cancer, and stroke. Although modern diagnostic techniques for detecting NDDs are varied, scientists are continuously seeking new and improved methods to enable early and precise detection. In addition to that, the present treatment options are limited to symptomatic therapy, which is effective in reducing the progression of neurodegeneration but lacks the ability to target the root cause—progressive loss of neuronal functioning. As a result, medical researchers continue to explore new treatments for these conditions. Here, we present a comprehensive summary of the key features of NDDs and an overview of the underlying mechanisms of neuroimmune dysfunction. Additionally, we dive into the cutting-edge treatment options that gene therapy provides in the quest to treat these disorders.

Ewing sarcoma (ES) is one of the most frequent types of malignant tumors among children. The active metabolic state of ES cells presents a new potential target for therapeutic interventions. As a primary regulator of cellular homeostasis, carbonic anhydrases (CAs; EC 4.2.1.1) have emerged as promising molecular targets for the development of anticancer drugs. Within the present study, we tested the commercial drug acetazolamide and our previously discovered inhibitors to target the CAII isoform, which was overexpressed and positively correlated with ES patient relapse. We employed molecular biology tests to identify effective inhibitors of CAII that can induce ferroptosis by downregulating FTH1 expression in ES cells. In vitro, we have also demonstrated their ability to reduce cell proliferation, decrease invasion, and induce apoptosis- or autophagy-related cell death. Using Western blotting, we confirmed the induction of cathepsin B in cells treated with CA inhibitors. It was found that the suppression of cathepsin B expression during the treatment reduces the anticancer efficacy of selected CAII inhibitors. These experiments highlighted profound antitumor activity of CAII inhibitors attributive to their remarkable ability to trigger ferroptosis in Ewing sarcoma cells without causing substantial host damage. The obtained results suggest that cytosolic CAII may be a prospective target for ES treatment, and CAII inhibitors can be considered as potential single-agent or combination antitumor agents to be used in the treatment of ES.

Purpose of Review: To critically synthesize proposed mechanisms underlying idiopathic neurodegeneration of substantia nigra (SN) neurons, emphasizing age-related vulnerability and neuron-specific physiological and biochemical characteristics. Recent Findings: We use inclusion (IN) and exclusion (EX) criteria. IN criteria (for the databases PubMed, Google Scholar, Scopus, and Cochrane, using the keywords “neurodegeneration AND substantia nigra,” “neuroinflammation AND substantia nigra,” “neurotoxic molecules AND neurodegeneration,” “activated microglia AND neuronal death,” “Parkinson disease,” and “problems OR unresolved problems OR questions AND Parkinson disease”): randomized controlled trials (RCTs), cohort studies, systematic reviews and meta-analyses, and experimental studies in vivo/in vitro. The timeframe is 2000–2025, and the language is English only. Only peer-reviewed journal articles with full text availability are included. EX criteria: articles that do not match PICO/PECO criteria, exist only in textbooks without proper approval, do not repeat studies, or have a very small sample size with no appropriate justification, or have a clear conflict of interest. AGREE II and AMSTAR tests were consolidated with three co-authors. Five primary hypotheses were identified to explain the pathogenesis of SN neurodegeneration: (1) dysfunction of the ubiquitin-proteasome system; (2) imbalance in cellular micro- and macronutrients, including iron dysregulation and ferritin accumulation; (3) involvement of neuropigments (neuromelanin and lipofuscin) in neuroinflammatory processes; (4) humoral neurotoxicity mediated by glutamate, dopamine, and metabolic byproducts; and (5) microglial activation and immune system engagement. These mechanisms were evaluated in the context of clinical observations, biochemical and physiological processes, and current treatment strategies. Economic and social impacts of neurodegenerative conditions were also assessed. Summary: The heterogeneity of SN neurons, their embryonic connectivity to both midbrain and prosomeric basal regions (P1–3), and the dual roles of neurotransmitters and neuropigments underscore the complexity of SN pathophysiology. Observed asymmetries in neurodegeneration, particularly in Parkinson’s disease, may reflect structural organization, differential innervation, and immuno-humoral regulation. Unlike previous studies addressing only general aspects of neurodegeneration, this analysis integrates cellular, molecular, and physiological perspectives, emphasizing mechanisms such as ferritin-mediated neurocytolysis, glial activation, and neurotransmitter toxicity. These insights advance understanding of SN neurodegeneration and may inform future therapeutic strategies.